Showing papers on "Quinolone published in 1990"

Nucleotide sequence and characterization of the Staphylococcus aureus norA gene, which confers resistance to quinolones.

Abstract: The norA gene cloned from chromosomal DNA of quinolone-resistant Staphylococcus aureus TK2566 conferred relatively high resistance to hydrophilic quinolones such as norfloxacin, enoxacin, ofloxacin, and ciprofloxacin, but only low or no resistance at all to hydrophobic ones such as nalidixic acid, oxolinic acid, and sparfloxacin in S. aureus and Escherichia coli. The 2.7-kb DNA fragment containing the norA gene had a long open reading frame coding for 388 amino acid residues with a molecular weight of 42,265, which was consistent with the experimental value of about 49,000 obtained on DNA-directed translation. The deduced NorA polypeptide has 12 hydrophobic membrane-spanning regions and is partly homologous to tetracycline resistance protein and sugar transport proteins. The uptake of a hydrophilic quinolone, enoxacin, by S. aureus harboring a plasmid carrying the norA gene was about 50% that by the parent strain lacking the plasmid, but it increased to almost the same level as that by the latter strain with carbonyl cyanide m-chlorophenyl hydrazone. On the other hand, the uptake of a hydrophobic quinolone, sparfloxacin, was similar in the two strains. These results suggest that the NorA polypeptide may constitute a membrane-associated active efflux pump of hydrophilic quinolones.

Quinolone Antibiotics in the Treatment of Salmonella Infections

Abstract: The 4-fluoroquinolones are a new class of antimicrobial agents that possess broad in vitro antibacterial activity, including efficacy against enteric pathogens such as Salmonella, Shigella, Campylobacter, Yersinia, and Vibrio species. These drugs are clinically effective against both drug-sensitive and multiresistant strains of Salmonella typhi and Salmonella paratyphi that cause enteric fever. In salmonella enterocolitis, the quinolones - unlike older antimicrobial agents that may have little impact on the duration of symptomatic illness and can in fact prolong fecal carriage of salmonellae - actually shorten the course of clinical disease and terminate excretion of these organisms in the stool. Similarly, for chronic carriers of both typhoidal and nontyphoidal Salmonella strains, the quinolones are effective in eradicating biliary and fecal reservoirs of infection. Immunosuppressed persons with salmonellosis, such as those with AIDS, may benefit from both short-term treatment and prolonged prophylaxis with a quinolone antibiotic. The optimal agent, dose, and duration of quinolone therapy for all salmonella syndromes remain to be determined by larger controlled trials.

Proportion of DNA gyrase mutants among quinolone-resistant strains of Pseudomonas aeruginosa.

Abstract: The proportion of DNA gyrase mutants among quinolone-resistant strains of Pseudomonas aeruginosa was examined by introducing the cloned wild-type Escherichia coli gyrA and gyrB genes. Of 101 spontaneous mutants of P. aeruginosa PAO505, 33 (33%) were found to have gyrA mutations. Among 17 clinical isolates, 12 (71%) had gyrA mutations and 1 (6%) had a gyrB mutation.

Quinolone inhibition of cytochrome P-450-dependent caffeine metabolism in human liver microsomes.

Abstract: Inhibitory effects of the quinolone antibiotics ofloxacin, lomefloxacin, pipemidic acid, ciprofloxacin, and enoxacin on caffeine metabolism were examined in vitro with human liver microsomes of four donors. All drugs competitively inhibited the activity of 3-demethylation, the major pathway of caffeine metabolism. Enoxacin, ciprofloxacin, and pipemidic acid were strong inhibitors exhibiting Ki values between 0.1 and 0.2 mM. Lomefloxacin and ofloxacin had moderate effects with Ki values of 1.2 and 3.6 mM, respectively. The rate of caffeine 7-demethylation (which amounted to about 25% of that for 3-demethylation) was only slightly affected by the quinolones. Minor, but inconsistent, effects were found on 8-oxidation to 1,3,7-trimethyluric acid. The results indicate that the reduction of caffeine clearance by concomitant quinolone application observed in vivo is primarily due to a competitive interaction of the inhibiting quinolones with the cytochrome P-450 isoenzyme(s) mediating caffeine demethylation.

In-vitro activity of sparfloxacin, a new quinolone antimicrobial agent

Abstract: The in-vitro activity of sparfloxacin (AT-4140), a new difluorinated quinolone, was compared with those of ciprofloxacin, temafloxacin and selected members of other groups of antimicrobial agents, against 651 recent distinct clinical isolates and strains with known mechanisms of resistance. Three strains of Chlamydia trachomatis were also studied. The MICs for 90% of the Enterobacteriaceae were between 0.06 and 1 mg/l; for Pseudomonas aeruginosa the MIC90 was 2 mg/l. Sparfloxacin was 16-fold more active against Acinetobacter spp. than ciprofloxacin. For Staphylococcus spp., Streptococcus, spp. and Enterococcus faecalis the MIC90 was between 0.25 and 1 mg/l; sparfloxacin was four-fold more active against Str. pneumoniae than ciprofloxacin. Ninety percent of strains of Haemophilus influenzae, Branhamella catarrhalis and Neisseria spp. were inhibited by less than 0.03 mg/l; for Bacteroides fragilis the MIC90 was 1 mg/l. The three strains of Chl. trachomatis were susceptible to 0.06-0.12 mg/l sparfloxacin, which was 16-fold more active than ciprofloxacin. There was cross resistance among the quinolones, but not between the quinolones and other groups of antimicrobials. The protein binding of sparfloxacin was 40% and serum had little effect on its activity.

DNA cloning and organization of the Staphylococcus aureus gyrA and gyrB genes: close homology among gyrase proteins and implications for 4-quinolone action and resistance.

Abstract: Staphylococcus aureus gyrA and gyrB genes, which encode the DNA gyrase A and B proteins, have been isolated and found to map contiguously. DNA sequence analysis revealed close homology between the S. aureus gyrase subunits and their counterparts in Bacillus subtilis and Escherichia coli, including several conserved amino acid residues whose substitution in E. coli confers resistance to 4-quinolones. These results are discussed in regard to quinolone resistance mechanisms in S. aureus.

The accumulation of five quinolone antibacterial agents by Escherichia coli

Abstract: The accumulation of five radiolabelled quinolone antibacterial agents by Escherichia coli KL16 was examined using a vacuum filtration method. Preliminary experiments were performed to determine the optimum quinolone concentration, inoculum of cells, filter washing regimen and filter type. All five quinolones showed a similar biphasic pattern of accumulation with high radioactive counts cell-associated during the first ten seconds of the assay, followed by steadily increasing accumulation over 30 min. Analysis of the mean accumulation after 30 min for each quinolone showed that there was no direct relationship between quinolone accumulation and antibacterial activity (as quantified by the MIC or bactericidal activity). Mechanistic investigations showed that accumulation was decreased by low reaction temperatures, acid pH and the presence of the metabolic inhibitors 2,4-dinitrophenol, potassium cyanide and sodium azide. These results suggest that quinolone accumulation by E. coli KL16 is partly dependent on cell metabolism and may proceed by an active transport mechanism. Treatment of cells with EDTA was found not to increase quinolone accumulation, suggesting that the outer membrane of E. coli KL16 does not act as a permeability barrier to these quinolones. The implication of these results in terms of possible mechanisms of bacterial resistance to quinolones is discussed.

Broad-host-range gyrase A gene probe.

Abstract: The Escherichia coli gyrase A gene was cloned in the broad-host-range cosmid vector pLA2917. The resulting plasmid, pNJR3-2, conferred quinolone susceptibility on a gyrA mutant of E. coli. To analyze the expression of this E. coli gene in Pseudomonas aeruginosa, pNJR3-2 or pLA2917 was mobilized via conjugation into P. aeruginosa PAO2 and several well-characterized quinolone-resistant mutants of this strain. The vector pLA2917 did not significantly affect the quinolone susceptibilities of any of the P. aeruginosa strains. However, pNJR3-2 conferred wild-type quinolone susceptibility on P. aeruginosa cfxA (gyrA) mutants and intermediate quinolone susceptibility on cfxA-cfxB double mutants of P. aeruginosa. The quinolone susceptibility of P. aeruginosa PAO2 gyrA+ was unaffected by pNJR3-2. Also, pNJR3-2 had no significant effect on P. aeruginosa cfxB (permeability) mutants. These results demonstrate that the DNA gyrase A gene from E. coli is expressed in P. aeruginosa and confers dominant susceptibility on gyrA mutants. Thus, pNJR3-2 can be used to detect the quinolone resistance mutations that occur in the gyrase A gene of this organism. pNJR3-2 also appears to discriminate between mutations in gyrA and mutations which alter permeability. This gyrase A probe was used successfully in the analysis of quinolone resistance in clinical isolates of P. aeruginosa.

Demonstration of quinolone phototoxicity in vitro.

Abstract: The ‘first-generation’ quinolones cinoxacin, nalidixic acid, oxolinic acid, pipemidic acid and rosoxacin and the newly developed quinolones ciprofloxacin, enoxacin, fleroxacin, norfloxacin and ofloxac

Potential mechanisms of resistance to the modern fluorinated 4-quinolones.

Abstract: The 4-quinolones are broad-spectrum antibiotics for which plasmid-mediated resistance has not yet been identified. Bacteria are able to develop resistance to these drugs via chromosomal mutations which result in an altered target (DNA gyrase) or reduced uptake of the drug (associated with alterations in the outer membrane)

New quinolone antibacterial agents. Synthesis and biological activity of 7-(3,3- or 3,4-disubstituted-1-pyrrolidinyl)quinoline-3-carboxylic acids.

Abstract: A series of 7-(3-amino- or 3-aminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-o xo-3-quinolinecarboxylic acids was synthesized and tested for antibacterial activity. Unique to these quinolones was the presence of a methyl or phenyl group in the pyrrolidine ring. Although the in vitro activity of these agents was usually equal to or less than that of their unsubstituted counterparts, one quinolone, 7-[3-(aminomethyl)-3-methyl-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid, displayed exceptional potency both in vitro and in vivo, particularly against Gram-positive organisms.

In vitro Activity of Temafloxacin Hydrochloride (TA-167 or A-62254), a New Fluorinated 4-Quinolone

Abstract: The in vitro antibacterial activity of temafloxacin hydrochloride (TA-167 or A-62254) was evaluated against a wide variety of clinical isolates and compared with those of other fluoroquinolones. The potency (MIC90) of the compound against gram-positive aerobic bacteria was higher or comparable to those of ciprofloxacin, ofloxacin, and norfloxacin. Against most gram-negative enteric bacteria and Pseudomonas species, temafloxacin was less active than ciprofloxacin, but was generally as active as ofloxacin and norfloxacin, except against Proteus species and Morganella morganii. Against obligate anaerobes, it was more active than the reference quinolones. Temafloxacin was bactericidal for one strain each of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. The compound inhibited E. coli DNA gyrase activity at a low concentration.

Pharmacokinetic and residue studies of quinolone compounds and olaquindox in poultry

Abstract: Nalidixic acid and similar antimicrobial agents have been available for more than 20 years, mainly for treating infections caused by Gram-negative enterobacteria. Recently, several chemically related drugs, including oxolinic acid, pipemidic acid, piromidic acid and flumequine, have been developed. They are either naphthyridine-carboxylic acid or quinoline-carboxylic acid derivatives and, with nalidixic acid, are so-called quinolones. A major advance in antimicrobial chemotherapy was the synthesis of newer quinolones containing at least 1 fluorine atom and a piperazinyl group. These new fluoroquinolones have an extended antimicrobial spectrum compared to the first quinolone generation, and are highly active against most Gram-negative pathogens including the Enterobacteriaceae and Pseudomonas aeruginosa. The pharmacokinetic properties and residue levels of these quinolones and fluoroquinolones for which clinical experience or experimental information exists in poultry are reviewed here. On the other hand, administration of the quinoxaline-di-N-oxide, olaquindox, for medical purposes raises questions concerning the pharmacokinetic disposition of the drug and the risk of its residues in poultry. This paper presents information about the pharmacokinetic profile of olaquindox and the presence of its residues in chickens.

Anti-bacterial quinolone- and naphthyridone-carboxylic acid compounds

Abstract: Quinolone compounds of the general formula ##STR1## pharmaceutical compositions active against bacterial infections containing such compounds, processes for the manufacture of the quinolone compounds and the compositions and the use of the quinolone compounds for the manufacture of pharmaceutical compositions for the treatment of bacterial infections.

Quinolones as Broad-spectrum Agents

Abstract: In a few short years, the new quinolone antimicrobial agents have been established as the therapy of many infections. It is reasonable to question whether this class of antimicrobial agent can truly be considered broad-spectrum in the way that the penicillins, cephalosporins, tetracyclines, chloramphenicol, and trimethoprim/sulfamethoxazole are. This report will review the characteristics of the new and future quinolones which show that these agents are broad-spectrum compounds.

Usual and unusual antibacterial effects of quinolones.

Abstract: Recently documented antibacterial effects of quinolones are reviewed. DNA gyrase is most likely to be the primary target site for these agents. Quinolones rapidly kill susceptible bacteria; the mechanisms of the bactericidal activity, still poorly understood, probably involve new protein synthesis. Quinolones alter membrane integrity before cell death, leading to leakage of cytoplasmic constituents. In Gram-negative bacteria, quinolones act as chelating agents for outer membrane divalent cations, disorganizing the bacterial lipopolysaccharide layer and facilitating the further entry of quinolone molecules in a 'self-promoted' pathway. Quinolones inhibit plasmid replication and reduce the efficacy of plasmid conjugation. Subinhibitory concentrations of quinolones can interfere with bacterial virulence factors, such as bacterial adherence to the host cell, phagocytosis and production of enzymes implicated in virulence. Recent studies also indicate synergism of quinolones with oxacillin against methicillin-resistant staphylococci and describe improved activity of newer compounds against Gram-positive pathogens.

Clostridium difficile-associated diarrhea after norfloxacin.

Abstract: Although theoretically the spectrum of antimicrobial quinolone antibiotics are at low risk of producing Clostridium difficile overgrowth and diarrhea, a patient developed this clinical problem while receiving norfloxacin. We review the antimicrobial activity of the quinolone antibiotics, with respect to their predisposition for producing C. difficile-induced diarrhea.

Enhancement of leucocyte killing of resistant bacteria selected during exposure to aminoglycosides or quinolones

Abstract: In vitro exposure to aminoglycosides and quinolones may select resistant subpopulations, although this is not a common clinical problem. This study was designed to determine whether aminoglycoside and quinolone resistant bacteria are more susceptible to leucocyte (WBC) killing. Cultures of Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus were pretreated with aminoglycosides (netilmicin, amikacin) and quinolones (enoxacin, ciprofloxacin) at 1/2 MIC for 24 h. The median susceptibility of bacteria selected during antibiotic exposure was reduced four-fold. These resistant subpopulations (10(6) cfu/ml) were exposed to 10(7) human WBC/ml for 6 h in antibiotic free cell culture media with 10% fresh human serum. Enhanced WBC activity was observed against all antibiotic pretreated bacteria in comparison with untreated controls (P less than 0.01). After 4 h of exposure to WBC, aminoglycoside or quinolone pretreated cultures of P. aeruginosa were reduced by 1.3-1.7 log, in comparison with a reduction of only 0.5 log in control cultures. These observations may explain in part the infrequent therapeutic failure with these drugs in hosts with competent neutrophils despite the potential of these drugs to select resistant strains in vitro.

In vitro activity of tosufloxacin, a new quinolone, against respiratory pathogens derived from cystic fibrosis sputum.

Abstract: By using broth microdilution methods, the in vitro activity of tosufloxacin (A-64730), a new quinolone, was compared with those of other agents, including five quinolones, against geographically diverse cystic fibrosis sputum isolates obtained from 26 cystic fibrosis centers in the United States. These included Pseudomonas aeruginosa, conventional as well as especially resistant (ceftazidime, aztreonam, gentamicin, and/or tobramycin) isolates: Escherichia coli; Pseudomonas cepacia; Staphylococcus aureus; and Haemophilus influenzae. Tosufloxacin MICs for 50 and 90% of isolates of standard P. aeruginosa were 0.5 and 2.0 mg/liter, for resistant P. aeruginosa they were 4.0 and greater than 16.0 mg/liter, for E. coli they were less than or equal to 0.016 mg/liter, for P. cepacia they were 4.0 and 8.0 mg/liter, for S. aureus they were 0.063 and 0.063 mg/liter, and for H. influenzae they were less than or equal to 0.016 and 0.032 mg/liter, respectively. Tosufloxacin activities against standard and resistant strains of P. aeruginosa were similar to those of comparative quinolones. Against E. coli, tosufloxacin activity was similar to those of other quinolones. Against S. aureus, tosufloxacin activity was similar to those of trimethoprim-sulfamethoxazole and cephalexin, but tosufloxacin was more active than other agents. Against H. influenzae, tosufloxacin activity was similar to those of other quinolones. There was minor diminution of activity at pH 8.2 but major diminution of activity at pH 5.2 and at inoculum sizes of greater than or equal to 10(7) CFU/ml. Activity was unaffected by sputum but was enhanced by serum and by the omission of cation supplementation. Tosufloxacin has consistent activity against common cystic fibrosis pathogens. Its high degree of activity against S. aureus with activity maintained against P. aeruginosa and other gram-negative bacteria of interest suggests that further in vitro studies and assessment of activity in in vivo models of cystic fibrosis pulmonary infections are warranted.

Selective Toxicity: The Activities of 4-Quinolones against Eukaryotic DNA Topoisomerases

Abstract: A number of new 4-quinolone antibacterials have been recently introduced for clinical use that have greater potency than the older analogs nalidixic acid and oxolinic acid (Andriole 1988; Bergan 1988). Like nalidixic acid, 4-quinolones are believed to inhibit bacterial growth by binding to the A subunit of DNA gyrase, a type II topoisomerase (Geliert et al. 1977). Since a homologous enzyme exists in the nucleus of eukaryotic cells, studies have been performed to examine the effects of 4-quinolones on this topoisomerase. Quinolones such as ciprofloxacin, norfloxacin, fleroxacin, and ofloxacin have, in general, been found to be only weak inhibitors of the eukaryotic enzyme in in vitro assays that measure the catalytic relaxation, unknotting, and catenation activities of the enzyme (Hussy et al. 1986; Riou et al. 1986). An alternative approach to assessing the effects of test agents on topoisomerases, involves measuring the extent of drug-enhanced DNA cleavage obtained in vitro in the presence of the enzyme. While DNA cleavage assays have been used to measure the effects of anti-tumour agents such as VP-16, VM-26, and ellipticine on eukaryotic topoisomerase II, 4-quinolones have not been extensively examined by this method. We have used four different topoisomerase II assay methods, including a non-radiolabeled DNA cleavage assay, for measuring the effects of some quinolones on purified calf thymus topoisomerase II. An experimental quinolone, CP-67,015, was found to elicit significant levels of DNA cleavage products in the presence of enzyme.

Comparisons of DNA Gyrases from Different Species

Abstract: Exposure of susceptible bacteria to 4-quinolones results in the rapid cessation of DNA replication and eventual cell lysis (Bourguignon et al. 1973; Crumplin and Smith 1986; Deitz et al. 1966; Relia and Haas 1982). The intrinsic susceptibility of different genera to quinolones, however, varies greatly (Barry and Jones 1984; Barry et al. 1984). In most cases inherent characteristics which influence susceptibility to quinolones have not been delineated. In assessing these differences one must first identify each component of the drug-cell interaction which contributes to quinolone activity. The analysis of quinolone resistance mutations in various bacteria have identified two important factors which affect susceptibility.

In vitro activities of irloxacin and E-3846, two new quinolones.

Abstract: Irloxacin and E-3846 are two new fluorinated quinolones. We evaluated the activities of these antimicrobial agents, ciprofloxacin, ofloxacin, enoxacin, pefloxacin, norfloxacin, and nalidixic acid against 1,161 bacterial strains. Ciprofloxacin was the most active quinolone. Irloxacin did not show great activity. The activity of E-3846 against gram-negative bacteria was similar to those of ofloxacin and pefloxacin, and E-3846 was the most active quinolone against gram-positive bacteria and anaerobes.

Use of an In Vitro DNA Strand-Breakage Assay to Monitor Compound Interactions with DNA Gyrase

Abstract: Topoisomerases are enzymes that regulate the superhelical density of DNA by transiently nicking either one (type I) or both (type II) strands of the DNA helix (Drlica 1984; Wang 1985; Osheroff 1989). DNA gyrase is a type II topoisomerase which catalyzes the ATP-dependent negative supercoiling of closed circular duplex DNA and is an essential enzyme in Escherichia coli (Geliert 1981). Gyrase actively maintains the supercoiled state of bacterial DNA and is involved in DNA replication, transcription, and recombination (Cozzarelli 1980). Escherichia coli DNA gyrase is an A2B2 tetramer; the A subunits mediate DNA breakage and rejoining, while the B subunits bind ATP and participate in energy transduction (Geliert 1981). The subunit A protein is the target of the quinolone family of antibacterial agents, and the newer fluoroquinolones, such as norfloxacin and ciprofloxacin, strongly inhibit the catalytic (strand-passing) activity of DNA gyrase. In the presence of oxolinic acid (as well as the newer 4-quinolone antibacterial agents), DNA gyrase forms a complex with DNA, which can be activated by treatment with detergent (e.g. SDS) to produce double-strand breaks in DNA. Detailed analyses of the broken complex have revealed that the break is a four-base stagger and that a gyrA subunit is covalently linked to each 5′ protruding end of the break (Morrison and Cozzarelli 1979; Fisher et al. 1981). The formation of this complex in vivo in the presence of drugs like norfloxacin presumably poisons DNA gyrase on the DNA template and thus inhibits cell growth (Higgins and Cozzarelli 1982).

New techniques for assessing pathogenicity of quinolone-resistant bacteria.

Abstract: Ciprofloxacin and ofloxacin-resistant variants of Staphylococcus aureus and Pseudomonas aeruginosa have been compared with their original drug-sensitive progenitor strains with respect to their susceptibility to opsonophagocytosis by human polymorphonuclear leucocytes. For strains exhibiting low level resistance to each quinolone some depression of chemiluminescence (respiratory burst) was recognized whereas for strains exhibiting high level resistance some potentiation of chemiluminescence occurred. There was no difference in terms of the phagocytic ingestion of each of the strains. This study provides only limited evidence to suggest that changes in bacterial virulence are associated with the development of resistance to the quinolone antimicrobials.

Azabicyclo quinolone carboxylic acids

Abstract: Having antibacterial activity by a group azabicyclo 7-substituted quinolone carboxylic acids.

Plasmid-Borne Resistance to 4-Quinolones a Real or Apparent Absence?

Abstract: The first quinolone, nalidixic acid, was introduced into clinical practice in the early 1960s. The 6-fluorinated quinolones, which are significantly superior, in particular in intrinsic activity and antibacterial spectrum, have been increasingly used since the 1970s. It is the purpose of this review to analyse why, in the early 1990s, plasmid-mediated resistance to quinolones has not yet been proven.

Quinolone-Resistant E. Coli Mutants Overproduce a 60 kDa Protein Highly Homologous to GroEL

Abstract: DNA gyrase is a member of a group of enzymes known as topoisomerases which are responsible for the control and modification of the topological state of DNA in vivo. E. coli DNA gyrase is composed of two A subunits and two B subunits of molecular masses 97 kDa and 90 kDa, coded for by the gyrA and gyrB genes respectively. DNA gyrase has been established as the likely target of the quinolone group of synthetic antibacterial drugs, which include nalidixic acid (NAL), oxolinic acid (OXO), norfloxacin (NFX) and ciprofloxacin (CFX). The quinolones have been found to be particularly useful in the treatment of urinary tract and enteric infections. Due to their success, there has been an extensive search for derivatives with broader spectra of bactericidal activities and improved pharmacological properties. Although it was previously thought that quinolone drugs bind to the A subunit, mutants conferring quinolone resistance have been mapped to both the gyrA and gyrB genes (Yamagishi et al. 1986; Yoshida et al. 1988). Other evidence has suggested that the drugs may preferentially bind to the gyrase-DNA complex (Shen et al. 1989).